Abstract
An efficient copper-catalyzed direct 2-arylation of benzoxazoles and benzoimidazoles with aryl bromides is presented. The CuI/PPh3-based catalyst promotes the installation of various aryl and heteroaryl groups through a C-H activation process in good to excellent yields. The cytotoxicity of obtained 2-aryl benzoxazoles (benzoimidazoles) was also evaluated and 1-methyl-2-(naphthalen-1-yl)benzoimidazole showed potential cytotoxicity.
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Introduction
2-Arylbenzoxazoles are important heterocyclic motif widely found in bioactive molecules1, pharmaceuticals2 and natural products3. 2-Substitued benzoxazoles are also fundamental scaffolds to construct novel ligands4,5,6,7 and materials8,9. As such, four main strategies for their preparation have been reported: (1) Transition metal-catalysed direct arylation of bezoxazoles with aryl halides10,11,12,13,14,15,16; (2) Intermolecular cyclization of 2-aminophenol with aldehydes17,18,19; (3) Intramolecular cyclization of halobenzanilides20,21; and (4) Ring-opening-coupling-recyclization of benzoxazoles with aromatic aldehydes or benzoyl chloride22,23. Among them, metal-catalysed direct arylation of C-H bond presents an economically attractive strategy to afford diverse 2-arylbenzoxazoles24,25,26,27,28. Convenient electrophiles, especially aryl halogens (ArX, X = Cl, Br, I), have been employed as the most widely used arylating reagents owing to their commercial availability and substituted diversity29,30,31,32.
Cross-coupling of benzoxazoles with aryl bromides catalysed by Palladium/Ligand system is an efficient protocol for the preparation of 2-arylbenzoxazoles33,34. Besides that, aryl chlorides are also an alternative coupling partner under Pd/N-heterocyclic carbene catalytic system (Fig. 1A)35. Except for noble metal Pd, cheap copper was found as qualified catalysis in the direct arylation of benzoxazoles with aryl iodides (Fig. 1B)11,12,36,37,38,39. Although efficiency, the synthesis of 2-arylbenzoxazoles via transition metal-catalysed direct arylation reaction with aryl halides suffered from the usage of noble metal or/and expensive aryl iodide. Recently, two copper-catalyzed direct arylation processes of benzoxazoles with aryl bromides were reported. But the employment of complex ligand13 or pre-preparation of nano-copper catalysis14 limited their widely application. Previously, we reported a room-temperature Pd/Nixantphos catalysed direct 2-arylation of benzoxazoles with aryl bromides34. In our continuous investigation on the metal catalysed synthesis 2-arylbenoxazoles, we report a Cu/PPh3-catalyzed direct 2-arylation of benzoxazoles with aryl bromides (Fig. 1C). At the same time, the cytotoxicity of afforded products is also tested.
Synthesis of 2-arylbenzoxazoles.
Results
We initiated the direct 2-aryation by testing six bases (LiOtBu, NaOtBu, KOtBu, Na2CO3, K2CO3, NaOH) in DMF at 135 °C for 8 hours under the CuI/PPh3 (10 mol%/20 mol%) catalytic system, using benzoxazole (1a, 1.0 equiv.) and 1-bromo-4-tert-butylbenzene (2a, 1.2 equiv., Table 1, entries 1–6). Interestingly, all the bases can promote the direct arylation to furnish corresponding coupling products 2-(4-(tert-butyl)phenyl)benzoxazole (3a), with K2CO3 affording the desired compound in 88% yield after 8 hours. Meanwhile, weaker base showed more efficiency than strong base, which suggested the pKa of 2-H is reduced via the chelation of Cu ion with Nitrogen atom of benzoxazole. When the ligand was changed from PPh3 to Phen (1,10-phenanthroline), Xantphos, or Nixantphos, the yields dropped dramatically (Table 1, entries 7–9). Screening of different copper sources in the arylation reaction indicated that only CuCl gave arylated product in 10% yield and Cu(II) almost cannot catalyse this coupling (Table 1, entries 10–12). Considering the Cu(I) need 3equiv. of PPh3 to form stable Cu(PPh3)3I complex, the loading of CuI/PPh3 was changed to 5 mol%/15 mol% and the ratio of 1a:2a was changed to 1.2:1, the coupling product 3a was afforded in 58% yield and unconverted benzoxazole 1a was detected (Table 1, Entry 13). Prolonging the reaction time to 24 h, the desired product 3a was isolated in 95% yield (Table 1, Entry 14). Finally, we found the combination of CuI (5 mol%), PPh3 (15 mol%), and K2CO3 (2.0 equiv) in DMF at 135 °C under nitrogen for 24 h as the best conditions for the direct arylation.
With the best conditions in hand, we endeavoured to prepare air-stable Cu(PPh3)3I complex (4) in gram scales firstly and apply them in the catalytic arylation reaction in order to simplify the operation process. Cu(PPh3)3I complex (4) crystals were easy afforded via reaction of CuI (1.0 equiv.) with PPh3 (3.0 equiv.) in anhydrous DMF at 45° C for 3 h. The single crystal of Cu(PPh3)3I complex (4) was resolved by X-ray diffraction for the first time (Fig. 2, CCDC 1497357). Unfortunately, stable Cu(PPh3)3I complex (4) crystal showed weaker catalytic efficiency than newly prepared catalysis solution under the best conditions and afforded 3a in 83% yield.
X-ray Structure of Cu(PPh3)3I (4).
Based on the optimized arylation conditions (Table 1, entry 14), we examined a variety of aryl bromides in the cross-coupling process using newly prepared CuI/ PPh3 solution as catalysis (Table 2). In general, the direct arylation of benzoxazole (1a) exhibited good yields with a range of aryl bromides. Electron neutral 1-bromo-4-tert-butylbenzene, the parent bromobenzene, and 2-bromonaphthalene furnished the desired products in 95, 92 and 98% yield, respectively. Aryl bromides bearing electron-donating methoxyl group led to the 2-(6-methoxynaphthalen-2-yl)benzoxazole (3d) in 88% yield. Electron withdrawing substituents (4-F, 4-Cl, 4-CF3, 3-CF3 and 3-CN) on the aryl bromide were well tolerated, providing products in 78–94% yields. It is worth mentioning that pyridine bromides, such as 3-bromopyridine, 3-bromo-5-methylpyridine, 2-bromopyridine, 4-bromopyridine and 2-bromoquinoline, were excellent arylated reagents with benzoxazole to afford corresponding 2- pyridylbenzoxazoles (3j–m) in 82–92% yields. Moreover, 2-bromoquinoline, 3-bromoquinoline and 4-bromoquinoline were also excellent coupling partners with benzoxazole to give bioactive biheterocyclic products (3n–p) in 90%, 84%, and 82% yields. Sadly, furan and thiophene compounds cannot survive under the conditions owing to the high reaction temperature.
Having demonstrated the broad scope of the aryl bromides in the arylation reaction, we then briefly explored the coupling of 5-methoxybenzoxazole (1b) and 1-methyl-1H-benzoimidazole (1c) with electron-withdrawing group substituted 1-bromo-4-chlorobenzene (2f), electron neutral 2-bromonaphthalene (2c), electron- donating group substituted 2-bromo-6-methoxynaphthalene (2d) and sterically hindered 1-bromonaphthalene (2m). To our delight, corresponding arylated products can be obtained in moderate to good yields (Table 3). We also tried the direct arylation of benzothiazole with aryl bromides under our optimized conditions but failed.
Benzo-azole derivatives are a class of important heterocyclic compounds possessing remarkable and various biological activity1,2. Therefore, the in vitro cytotoxicity of obtained 2-aryl benzoxazoles and benzoimidazoles analogues against several human cancer cell lines was evaluated by classic MTT methods using paclitaxel as positive control (Table 4). Interestingly, all the 2-arylbenzoxazoles exhibited totally inactivity except for quinolinylbenzoxazoles (3n–p) showing weak cytotoxicity against BGC-823. In contrast, most of 2-arylbenzoimidazoles (3t–v) displayed potential cytotoxicity against BGC-823 but inactivity of 2-(4-chlorophenyl)-1-methyl-1H-benzoimidazole (3s). Comprehensive analysing the structure-activity relationship (SAR) of 2-aryl benzoxazoles and benzoimidazoles, we can draw the conclusion that: 1) Nitrogen atom is the essential to keep the cytotoxicity. 2) Big substituted groups at C-2 position contribute to the increasing of cytotoxicity. Based on the preliminary SAR results, we will design, synthesis and biological evaluation more N-alkyl-2-heterocycilic aryl benzoimidazoles analogues in our continuous research.
Discussion
In summary, we have demonstrated a copper-catalysed direct 2-arylation of benzoxazoles and benzoimidazoles with aryl bromides. The cheap copper catalysis and PPh3 ligand promoted the cross-coupling reaction in good to excellent yields with broad substrate scope, which provides a promising method for the synthesis of pharmacologically significant 2-aryl benzoxazoles and benzoimidazoles derivatives. Meanwhile, preliminary cytotoxicity and SAR results of afforded products will give important guideline in the medicinal chemistry community of azoles.
Methods
General Information
All reactions were conducted under an inert atmosphere of dry argon. All reagents were purchased from TCI and used without further purification. N,N-Dimethylformamide (DMF), toluene and xylene were dried through activated 4 Å Molecular Sieves under argon. 1,4-dioxane was dried through calcium hydride and tetrahydrofuran (THF) with sodium. Solvents were commercially available and used as received without further purification. Reactions were monitored by thin layer chromatography (TLC) on silica gel plates (GF 254) using UV light to visualize the course of the reactions. NMR spectra were obtained using a Brüker 400 MHz Fourier-transform NMR spectrometer. High resolution mass spectrometry (HRMS) data were obtained on a Waters LC-TOF mass spectrometer (model LCT-XE Premier) using chemical ionization (CI) or electrospray ionization (ESI) in positive or negative mode, depending on the analyze. Chemical shifts (δ) are reported in ppm with TMS as internal standard. Abbreviations for signal couplings are: s, singlet; d, doublet; t, triplet; m, multiplet.
General Procedure for the Cu-catalyzed arylation of benzoxazoles and benzoimidazoles
An oven-dried 10 mL reaction vial equipped with a stir bar was charged with benzoxazole (0.5 mmol) and K2CO3 (138.0 mg, 1.0 mmol, 2 equiv), and then sealed with a rubber stopper under an argon atmosphere. A solution (from a stock solution) of CuI (4.76 mg, 0.025 mmol) and PPh3 (19.7 mg, 0.075 mmol) in 1 mL of dry DMF was taken up by syringe and added to the reaction vial. Preparation of the stock solution from CuI (23.8 mg, 0.125 mmol) and PPh3 (98.4 mg, 0.375 mmol) in 5 mL of dry DMF was stirred for 1 h at 135 °C under argon. Aryl bromide (0.6 mmol, 1.2 equiv) was added to the reaction mixture by syringe. Note that solid aryl bromides were added to the reaction vial prior to addition of K2CO3. The reaction mixture was stirred for 24 h at 135 °C, quenched with two drops of H2O, diluted with 3 mL of ethyl acetate, and filtered over a pad of Na2SO4 and silica. The pad was rinsed with additional ethyl acetate, and the solution was concentrated in vacuo. The crude material was loaded onto a silica gel column and purified by flash chromatography.
Determination of cell viability by MTT assay
Cells were plated in the RPMI 1640 with 10% fetal calf serum media on 96-well plates in a total volume of 100 μL with a density of 1 × 104 cells mL−1. Triplicate wells were treated with media and tested compounds. The plates were incubated at 37 °C in 5% CO2 for 72 h. Cell viability was determined based on mitochondrial conversion of 3[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT, Sigma) to formazan. The amount of MTT converted to formazan is a sign of the number of viable cells. Each well was supplemented with 50 mL of a 1 mg mL−1solution of MTT in uncompleted media. The plates were incubated in 37 °C, 5% CO2 for an additional 4 h. The media was carefully removed from each well and then 200 μL of DMSO was added. The plates were gently agitated until the reaction color was uniform and the OD570 was determined using a microplate reader (Wellscan MK3, Labsystems Dragon). Microsoft® Excel 2010 was used to analyze data. Media-only treated cells served as the indicator of 100% cell viability. The 50% inhibitory concentration (IC50) was defined as the concentration that reduced the absorbance of the untreated wells by 50% of the control in the MTT assay.
2-(4-tert-Butylphenyl)benzoxazole (3a)
White solid (119 mg, 95% yield); 1H NMR (400 MHz, CDCl3): δ = 8.22 (d, J = 8.5 Hz, 2H), 7.81–7.79 (m, 1H), 7.62–7.57 (m, 3H), 7.38–7.36 (m, 2H), 1.40 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3): δ = 163.3, 155.1, 150.7, 142.2, 127.5, 125.9, 124.9, 124.5, 124.4, 119.9, 110.5, 35.1, 31.2 ppm. The 1H and 13C NMR data for this compound match the literature data34.
2-Phenylbenzoxazole (3b)
White solid (89 mg, 92% yield); 1H NMR (400 MHz, CDCl3): δ = 8.30–8.28 (m, 2H), 7.82–7.80 (m, 1H), 7.63–7.60 (m, 1H), 7.57–7.55 (m, 3H), 7.40–7.37 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ = 163.1, 150.8, 142.1, 131.5, 128.9, 127.6, 127.2, 125.1, 124.6, 120.0, 110.6 ppm. The 1H and 13C NMR data for this compound match the literature data34.
2-(Naphthalen-2-yl)benzoxazole (3c)
Yellow solid (120 mg, 98% yield); 1H NMR (400 MHz, CDCl3): δ = 8.80 (s, 1H), 8.34 (dd, J = 8.6 Hz, 1.7 Hz, 1H), 8.02–7.98 (m, 2H), 7.92–7.90 (m, 1H), 7.85–7.83 (m, 1H), 7.66–7.58 (m, 3H), 7.41–7.39 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ = 163.2, 150.9, 142.2, 134.8, 133.0, 129.0, 128.8, 128.2, 127.9, 127.8, 126.9, 125.2, 124.7, 124.4, 124.0, 120.1, 110.6 ppm. The 1H and 13C NMR data for this compound match the literature data34.
2-(6-Methoxynaphthalen-2-yl)benzoxazole (3d)
Yellow solid (121 mg, 88% yield); 1H NMR (400 MHz, CDCl3): δ = 8.68 (s, 1H), 8.27 (dd, J = 8.6 Hz, 1.6 Hz, 1H), 7.88–7.80 (m, 3H), 7.62–7.60 (m, 1H), 7.38–7.36 (m, 2H), 7.22 (dd, J = 8.9 Hz, 2.5 Hz, 1H), 7.16 (s, 1H), 3.94 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ = 163.5, 159.2, 150.8, 142.3, 136.3, 130.5, 128.4, 128.0, 127.5, 124.9, 124.6, 124.6,122.2, 119.8, 119.8, 110.5, 105.9, 55.4 ppm. HRMS calculated for C18H14NO2, 276.1025, found 276.1038, [M+H]+.
2-(4-Fluorophenyl)benzoxazole (3e)
Yellow solid (93.7 mg, 88% yields); 1H NMR (400 MHz, CDCl3): δ = 8.30–8.27 (m, 2H), 7.80–7.78 (m, 1H), 7.61–7.59(m, 1H), 7.39–7.37 (m, 2H), 7.26–7.22 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ = 164.8 (d, J = 252.8 Hz), 162.2, 150.8, 142.1, 129.9 (d, J = 8.9 Hz), 125.2, 124.7, 123.5, 120.0, 116.2 (d, J = 22.2 Hz), 110.6 ppm. The 1H and 13C NMR data for this compound match the literature data34.
2-(4-Chlorophenyl)benzoxazole (3f)
White solid (99.6 mg, 87% yield); 1H NMR (400 MHz, CDCl3): δ = 8.19 (d, J = 8.7 Hz, 2H), 7.80–7.78 (m, 1H), 7.60–7.58 (m, 1H), 7.52–7.50 (d, J = 8.7 Hz, 2H), 7.39–7.37 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ = 162.1, 150.8, 142.0, 137.8, 129.3, 128.9, 125.7, 125.4, 124.87, 120.1, 110.6 ppm. The 1H and 13C NMR data for this compound match the literature data34.
2-(4-(Trifluoromethyl)phenyl)benzoxazole(3g)
White solid. (111.7 mg, 85% yield); 1H NMR (400 MHz, CDCl3): δ = 8.39 (d, J = 8.1 Hz, 2H), 7.84–7.80 (m, 3H), 7.65–7.62 (m, 1H), 7.43–7.41 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ = 161.5, 150.9, 141.9, 133.0 (m, J = 32.8 Hz), 130.5, 127.9, 125.9 (m, J = 3.8 Hz), 125.8, 125.0, 122.4, 120.4, 110.8 ppm. The 1H and 13C NMR data for this compound match the literature data36.
2-(3-(trifluoromethyl)phenyl)benzoxazole (3h)
White solid (102.5 mg, 78% yield); 1H NMR (400 MHz, CDCl3): δ = 8.55 (s, 1H), 8.44 (d, J = 7.8 Hz, 1H), 7.83–7.80 (m, 2H), 7.70–7.62 (m, 2H), 7.42–7.40 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ = 161.5, 150.8, 141.9, 131.6 (m, J = 32.7 Hz), 130.6, 129.5, 128.0, 127.9 (dd, J = 7.3 Hz, 3.6 Hz), 125.7, 124.9, 124.5 (m, J = 3.8 Hz), 122.4, 120.3, 110.8 ppm. The 1H and 13C NMR data for this compound match the literature data34.
3-(benzoxazol-2-yl)benzonitrile (3i)
White solid (103.4 mg, 94% yield); 1H NMR (400 MHz, CDCl3): δ = 8.55 (s, 1H), 8.48 (d, J = 8.0 Hz, 1H), 7.83–7.81 (m, 2H), 7.69–7.65 (t, J = 8.0 Hz, 1H), 7.64–7.62 (m, 1H), 7.44–7.41 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ = 160.6, 150.8, 141.8, 134.4, 131.4, 131.0, 129.9, 128.6, 126.0, 125.1, 120.5, 117.9, 113.5, 110.9 ppm. The 1H and 13C NMR data for this compound match the literature data40.
2-(pyridin-3-yl)benzoxazole(3j)
White solid (84.2 mg, 86% yield); 1H NMR (400 MHz, CDCl3): δ = 9.46 (s, 1H), 8.75 (dd, J = 4.8 Hz, 1.5 Hz, 1H), 8.49 (d, J = 8.0 Hz, 1H), 7.79–7.77 (m, 1H), 7.60–7.58 (m, 1H), 7.46–7.44 (m, 1H), 7.38–7.36 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ = 160.6, 152.0, 150.7, 148.8, 141.8, 134.7, 125.7, 124.9, 123.7, 123.6, 120.3, 110.8 ppm. The 1H and 13C NMR data for this compound match the literature data41.
2-(5-methylpyridin-3-yl)benzoxazole (3k)
White solid (86.1 mg, 82% yield); m.p. = 110–112 °C; 1H NMR (400 MHz, CDCl3): δ = 9.28 (s, 1H), 8.60 (s, 1H), 8.34 (s, 1H), 7.80–7.79 (m, 1H), 7.63–7.60 (m, 1H), 7.40–7.38 (m, 2H), 2.46 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ = 161.0, 152.7, 150.7, 146.0, 141.8, 135.1, 133.5, 125.6, 124.9, 123.0, 120.2, 110.8, 18.4 ppm; IR (thin film): 3116, 1560, 1529, 1454, 1441, 1244, 1201, 1118, 1015, 819 cm−1; HRMS calculated for C13H11N2O, 211.0871, found 211.0882, [M+H]+ .
2-(pyridin-2-yl)benzoxazole (3l)
White solid (90.0 mg, 92% yield); 1H NMR (400 MHz, CDCl3): δ = 8.80 (s, 2H), 8.34 (d, J = 8.0 Hz, 1H), 7.87 (t, J = 8.0 Hz, 1H), 7.84–7.78 (m, 1H), 7.68–7.58 (m, 1H), 7.46–7.34 (m, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ = 161.4, 151.0, 150.3, 146.0, 141.7, 137.0, 126.0, 125.5, 124.9, 123.4, 120.6, 111.2 ppm. The 1H and 13C NMR data for this compound match the literature data10.
2-(pyridin-4-yl)benzoxazole (3m)
Yellow solid (87.2 mg, 89% yield); 1H NMR (400 MHz, CDCl3): δ = 8.8 (s, 2H), 8.08 (d, J = 6.0 Hz, 1H), 7.85–7.79 (m, 1H), 7.65–7.58 (m, 1H), 7.48–7.36 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ = 160.6, 150.9, 150.7, 141.7, 134.3, 126.3, 125.1, 121.0, 120.7, 110.9 ppm. The 1H and 13C NMR data for this compound match the literature data10.
2-(isoquinolin-3-yl)benzoxazole (3n)
Yellow solid (110.7 mg, 90% yield); 1H NMR (400 MHz, CDCl3): δ = 8.48 (d, J = 8.4 Hz, 1H), 8.36(d, J = 8.4 Hz, 2H), 7.89 (t, J = 8.4 Hz, 2H), 7.82 (dt, J1 = 8.4 Hz, J2 = 1.6 Hz, 1H), 7.78–7.71 (m, 1H), 7.68–7.62 (m, 1H), 7.50–7.41 (m, 2H) ppm; 13C NMR (101 MHz, CDCl3) δ = 161.6, 151.3, 148.1, 145.9, 141.8, 137.3, 130.4, 130.3, 128.7, 128.1, 127.7, 126.3, 125.0, 120.8, 120.3, 111.5 ppm. The 1H and 13C NMR data for this compound match the literature data10.
2-(Quinolin-4-yl)benzoxazole (3o)
Yellow solid (103.3 mg, 84% yield); 1H NMR (400 MHz, CDCl3): δ = 9.46 (d, J = 6.8 Hz, 1H), 9.43 (s, 1H), 9.36 (s, 1H), 8.06 (d, J = 6.8 Hz, 1H), 7.91 (t, J = 6.8 Hz, 1H), 7.89–7.85 (m, 1H), 7.71 (t, J = 6.8 Hz, 1H), 7.69–7.63 (m, 1H), 7.46–7.37 (m, 2H) ppm; 13C NMR (101 MHz, CDCl3) δ = 161.0, 155.6, 150.1, 145.2, 142.0, 132.8, 132.2, 128.4, 128.3, 127.9, 125.7, 125.6, 124.7, 120.3, 117.8 ppm. The 1H and 13C NMR data for this compound match the literature data34.
3-Benzooxazol-2-ylquinoline (3p)
Yellow solid (100.8 mg, 82% yield); 1H NMR (400 MHz, CDCl3): δ = 9.75 (s, 1H), 9.00 (s, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.86–7.81 (m, 2H), 7.67–7.63 (m, 2H), 7.43–7.41 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ = 161.0, 150.8, 149.1, 148.6, 141.9, 135.3, 131.3, 129.6, 128.7, 127.7, 127.2, 125.7, 125.0, 120.4, 120.3, 110.8 ppm. The 1H and 13C NMR data for this compound match the literature data42.
2-(4-Chlorophenyl)-5-methoxybenzoxazole (3q)
Yellow solid (108.7 mg, 84% yield); m.p. = 120–121 °C; 1H NMR (400 MHz, CDCl3): δ = 8.18 (d, J = 8.7 Hz, 2H), 7.53–7.46 (m, 3H), 7.27 (d, J = 2.5 Hz, 1H), 7.00–6.97 (m, 1H), 3.90 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ = 162.8, 157.5, 145.4, 142.8, 137.7, 129.3, 128.7, 125.8, 114.0, 110.8, 102.9, 56.0 ppm. IR (thin film): 1626, 1567, 1468, 1322, 1234, 1155, 998, 816 cm−1; HRMS calculated for C14H11ClNO2, 260.0478, found 260.0482, [M+H]+.
5-Methoxy-2-(naphthalen-2-yl)benzoxazole (3r)
Yellow solid (121 mg, 88% yield); m.p. = 136–137 °C; 1H NMR (400 MHz, CDCl3): δ = 8.78 (s, 1H), 8.32 (dd, J = 8.6 Hz, 1.6 Hz, 1H), 8.02–7.91(m, 3H), 7.63–7.57 (m, 2H), 7.52 (d, J = 8.9 Hz.1H).7.32 (d, J = 2.5 Hz, 1H), 7.00 (dd, J = 8.9 Hz, 2.5 Hz, 1H), 3.92 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ = 164.0, 157.5, 145.6, 143.1, 134.7, 133.0, 128.9 (d, J = 18.3 Hz), 128.0–127.7 (m), 126.9, 124.5, 123.9, 113.8, 110.7, 102.9, 56.0 ppm. IR (thin film): 3081, 3005, 1565, 1502, 1437, 1409, 1325, 1211, 1006, 867 cm−1; HRMS calculated for C18H14NO2, 276.1025, found 276.1029, [M+H]+.
2-(4-Chlorophenyl)-1-methyl-1H-benzoimidazole(3s)
White solid (98 mg, 81% yield) as a. 1H NMR (400 MHz, CDCl3): δ = 7.85–7.83 (m, 1H), 7.73 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 8.6 Hz, 2H), 7.41–7.39 (m, 1H), 7.36–7.33 (m, 2H), 3.86 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ = 152.6, 142.9, 136.6, 136.0, 130.7, 129.0, 128.7, 123.1, 122.7, 119.9, 109.7, 31.7 ppm. The 1H and 13C NMR data for this compound match the literature data43.
1-Methyl-2-(naphthalen-2-yl)-1H-benzoimidazole (3t)
Yellow solid (109.6 mg, 85% yield); m.p. = 129–130 °C; 1H NMR (400 MHz, CDCl3): δ = 8.28 (s, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.98–7.90 (m, 4H), 7.61–7.58 (m, 2H), 7.46–7.44 (m, 1H), 7.38–7.36 (m, 2H), 3.95(s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ = 153.8, 143.1, 136.7, 133.6, 133.0, 129.4, 128.6, 128.5, 127.9, 127.6, 127.3, 126.8, 126.4, 122.9, 122.6, 119.9, 109.7, 31.9 ppm. IR (thin film): 1738, 1567, 1133, 1006, 748 cm-1; HRMS calculated for C18H15N2, 259.1235, found 259.1239, [M+H]+.
2-(6-Methoxynaphthalen-2-yl)-1-methyl-1H-benzoimidazole (3u)
Yellow solid (118.0 mg, 82% yield); m.p. = 131–132 °C; 1H NMR (400 MHz, CDCl3): δ = 8.20 (s, 1H), 7.91–7.85 (m, 4H), 7.44–7.42 (m, 1H), 7.37–7.34 (m, 2H), 7.26–7.22 (m, 2H), 3.98 (s, 3H), 3.94 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ = 158.7, 154.0, 143.1, 136.7, 135.1, 130.1, 129.2, 128.5, 127.3, 126.9, 125.3, 122.7, 122.5, 119.8, 119.7, 109.6, 105.7, 55.4, 31.9 ppm. IR (thin film): 1622, 1514, 1433, 1401, 1206, 1148, 1118, 1006, 804 cm−1; HRMS calculated for C19H17N2O, 289.1341, found 289.1349, [M+H]+.
1-Methyl-2-(naphthalen-1-yl)-1H-benzoimidazole (3v)
White solid (96.7 mg, 75% yield); 1H NMR (400 MHz, CDCl3): δ = 8.05 (d, J = 8.2 Hz.1H), 7.98 (d, J = 7.6 Hz.1H), 7.94–7.92 (m, 1H), 7.75 (d, J = 8.3 Hz.1H), 7.71 (dd, J = 7.0 Hz, 1.2 Hz, 1H), 7.65–7.61 (m, 1H), 7.59–7.48 (m, 3H), 7.42–7.39 (m, 2H), 3.65 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ = 152.9, 143.2, 135.9, 133.6, 132.2, 130.3, 128.9, 128.5, 127.8, 127.2, 126.4, 125.5, 125.1, 122.9, 122.4, 120.1, 109.6, 31.1 ppm. The 1H and 13C NMR data for this compound match the literature data44.
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How to cite this article: Jia, N.-N. et al. Copper-catalyzed Direct 2-Arylation of Benzoxazoles and Benzoimidazoles with Aryl Bromides and Cytotoxicity of Products. Sci. Rep. 7, 43758; doi: 10.1038/srep43758 (2017).
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Acknowledgements
Financial support from NSFC (No. 31570341) and Key Technology Program from Scihuan Provice, China (No. 2015SZ0105) is greatly appreciated.
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F.G. and X.-L.Z. initiated and designed the project. S.H. contributed to study design, coordinated the project, and cytotoxicity assay. N.-N.J., X.-C.T., X.-X.Q. performed the synthesis of these compounds. X.-X.C. and Y.-X.Y. contributed to bioassay. Y.-N.C. helped with data analysis and manuscript preparation. All authors reviewed the manuscript.
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Jia, NN., Tian, XC., Qu, XX. et al. Copper-catalyzed Direct 2-Arylation of Benzoxazoles and Benzoimidazoles with Aryl Bromides and Cytotoxicity of Products. Sci Rep 7, 43758 (2017). https://doi.org/10.1038/srep43758
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DOI: https://doi.org/10.1038/srep43758
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